Retinoids and Retinoid Receptors in Teratogenesis*

There is overwhelming evidence that vitamin A (retinol), presumably through its metabolite retinoic acid, participates in organogenesis at several stages and sites during normal development. Besides the important role of retinol and retinoic acid (RA) as micronutrients in growth and development, these retinoids and their synthetic analogs are now viewed as drugs for treatment of oncologic and dermatologic diseases. An excess of vitamin A, RA, or several other synthetic analogs are teratogenic. Mechanisms involved in teratogenesis remain unsolved but are under active investigation in many laboratories. The attention has recently focused on a series of endogenous proteins which serve as nuclear receptors for natural retinoids as means to discover how retinoids intervene in diverse cellular functions and which of their cellular and molecular targets are crucial to the developing embryo. There are two classes of receptors, termed retinoic acid receptors (RARs) and retinoid X receptors (RXRs). This brief review summarizes the results of our recent studies which suggest that: 1) the teratologic effects of retinoids are mediated by the nuclear receptors; 2) the heterodimer RXR/RAR pathway is the major mechanism for the induction of teratogenesis; 3) RXR-selective synthetic retinoids have diminished teratogenicity; and 4) an overexpression of specific RARs in response to RA disrupt skeletal morphogenesis resulting in limb reduction defects.